PL211301B1 - Orally-dispersible multilayer tablet - Google Patents

Abstract

The present invention relates to a multilayer orodispersible tablet and to the process for preparing it.

Description

(12) PATENT DESCRIPTION (19) PL (11) 211301 (13) B1 (21) Application number: 379425 (51) Int.Cl.

(22) Filing date: June 4, 2004 A61K 9/20 (2006.01) (86) Date and number of the international application:

04.06.2004, PCT / FR04 / 001400 (87) Date and publication number of the international application:

23.12.2004, WO04 / 110411 (54) Orally dispersible multilayer tablet and the method of its preparation

(73) The right holder of the patent: (30) Priority: 2003-06-06, FR, 03/06900 2003-06-30, US, 10 / 610,668 ETHYPHARM, Houdan, FR (72) Inventor (s): PASCAL OURY, Le Chesney, FR (43) Application was announced: GAEL LAMOUREUX, Le Boullay Thierry, FR September 18, 2006 BUP 19/06 CATHERINE HERRY, Marcilly-sur-Eure, FR YANN PREVOST, Tremblay-Les-Villages, FR (45) The grant of the patent was announced: May 31, 2012 WUP 05/12 (74) Representative: item. stalemate. Ewa Gromek

PL 211 301 B1

Description of the invention

The invention relates to an orally dispersible multilayer tablet and a process for its preparation, more particularly a tablet with at least two layers containing at least one active substance and a mixture of excipients.

The term "orodispersible tablet" means that the tablet is able to disperse or dissolve in the mouth without chewing or chewing, on contact with saliva in less than 60 seconds, preferably in less than 40 seconds, forming a suspension of particles that is easy to swallow.

Disintegration time is the time between the time the tablet is placed on the tongue and the time the suspension, which has broken up or dissolved, is swallowed.

This type of tablet is described, for example, in EP 548 356, EP 636 364, EP 1 003 484, EP 1 058 538, WO 98/46215, WO 00/06126, WO 00/27357 and WO 00/51568.

After swallowing, particles of the active substance are released into the lower parts of the gastrointestinal tract.

Due to its ease of use, the orodispersible tablet is perfectly suitable for outpatient treatment, especially for some patients, especially for elderly people or children who have difficulty swallowing and find it unpleasant or impossible to swallow the tablet. or gel capsules, whether or not with simultaneous liquid intake.

It is estimated that 50% of the population experiences such difficulties and, due to possible consequences, the described medicinal product is not used, thus reducing the effectiveness of the treatment. (H. Seager, 1998, J. Pharm, Pharmacol. 50, 375-382).

Swallowing difficulties are of course made worse when multiple medications are given throughout the day, hence multiple dosing throughout the day.

The orodispersible tablets containing the combination of the active ingredient will take the form of a solution for better patient compliance during a longer period of treatment, especially in chronic conditions affecting the elderly or children.

Attempts to prepare such tablets have been and are made, for example, by tableting a single mixture containing excipients and active substances. However, such tablets have some drawbacks, in particular they show a lack of uniform content for each ingredient, or they risk incompatibility between different tablet ingredients, active ingredients and excipients.

The main technical difficulty of the process is to obtain a uniform content of ingredients in the entire tablet during the production process, by tableting a powder mixture of all tablet ingredients.

A powder mixture is difficult to control because it is made up of multiple populations of active ingredients and excipients having their own size, density or shape characteristics.

This non-uniformity of the material increases the risk of separation as reflected by the gradual "detachment of certain populations of particles during storage or in the feed hopper of the tabletting device."

The final uniformity is created with the great variety of active ingredients contained, with their own hardness, disintegration, or softness characteristics which are significantly different from batch to batch.

The detailed breakdown of the active ingredient and excipient populations is not sufficient to completely eliminate this risk.

Moreover, other solutions suitable for orodispersible tablets proposed for improving the uniformity of the tablet composition, for example in patent application FR 03 01 308 (not published so far), are not entirely sufficient to limit the risk of incompatibility.

A second technical difficulty in the production of a tablet containing an active ingredient combination is making the right choice of active ingredients and excipients that can be used together, taking into account the risk of incompatibilities between themselves or between the active ingredients and excipients. The risk increases with more ingredients in the tablet.

In order to reduce the risk of incompatibility, it is proposed to use solutions, especially when preparing multilayer tablets. Such tablets have been known for many years (Abrege de Pharmacie Galenique [Abstract of Pharmaceutical Pharmacy], Le Hir, 3rd edition page 269, Evaluation of bilayer

PL 211 301 B1 tablet machines - A case study. S.P. Li, M.G. Karth, K.M. Feld, L.C. Di Paolo, CM. Pendharkar, R.O. Williams Drug Dev. Indium. Pharm., 21 (5), 571-590 (1995)).

They are made of at least two layers with surfaces adjacent to each other.

Each tablet layer has its own composition and is successively formulated by tableting, which reduces both the risk of tablet non-uniformity and lack of physical and chemical compatibility.

However, this method of tablet formulation requires good adhesion of the various layers.

In this case, it is helpful to apply high compression forces, which are often greater than 100 N, to obtain a tablet with high hardness, or to use binders in at least one tablet layer in an amount effective to enhance inter-layer adhesion.

Moreover, the manufacture of a multilayer tablet requires the application of a uniform reproducible compressive force to each powder mixture.

Therefore, the conditions of the above processes are not very favorable, either in the case of tablets with a tendency to disintegrate quickly or in the case of active substances that require masking their bitter taste. The bitter taste is masked by agents such as polymer coatings, which are known to be particularly sensitive to compression, and their use is incompatible with the process conditions, which require the application of compression forces, which increases the risk of breakage of the shell.

And this is the reason today that among the solid forms that disintegrate in the mouth, only multilayer tablets, which exist in the form of tablets or lozenges, for the local administration of active substances limited to the mucosa of the cheek and oropharynx, do not require a taste masking agent other than simply adding sweeteners.

One known example of such tablets for sublingual administration is Solutricine® Vitamin C sold in France by Theraplix which is a triple layer tablet containing tyrothricin and ascorbic acid.

These multilayer lozenges have a high level of hardness for achieving good layer adhesion, and have a residence time of several minutes in the mouth which corresponds to the gradual disintegration time of the tablet.

Erosion and solubility, which constitute the main disintegration mechanism of such a tablet, directly depend on the size of the tablet and the size of the surface area in contact with the saliva.

The above limitations force the situation that the solutions proposed for the preparation of combinations of active substances cannot be used for orally dispersible tablets, even more so when it is necessary to mask the taste of the active substances used.

WO 03/017985 describes a bilayer tablet which is dispersed for 3 minutes in aqueous fluids prior to administration and then administered with a spoon. Therefore, it is not recommended to disintegrate this tablet and dissolve in the mouth for disintegration. Moreover, the method of its production does not include a pre-compression step.

Therefore, there is a need to develop orodispersible tablets that allow the combination of different active substances, tablets that are optionally coated, without the drawbacks of tablet formulation non-uniformity or incompatibility. The Applicant has found that, contrary to existing findings and predictions, it is possible to obtain a multi-layer orodispersible tablet.

The invention therefore relates to an orodispersible tablet having at least two layers, each layer containing at least one active substance and an excipient mixture comprising, based on the weight of each tablet layer;

- 20 to 90% at least one soluble agent selected from the group consisting of sugars, polyols with less than 13 carbon atoms, and mixtures thereof;

- 1 to 20% at least one tablet disintegrant;

- up to 2% of a slip agent; and

- 1 to 15% at least one swelling agent, said tablet having a hardness from 1 kp (9.8N) to 6 kp (58.8N), a brittleness of less than 1%, and which is capable of disintegrating or dissolving in the mouth without chewing in contact with saliva in less than 60 seconds, forming particles of a suspension that are easily swallowed.

The tablet preferably comprises 2 or 3 layers. The tablet preferably comprises 3 layers and only the two outer layers contain at least one active substance. In addition, each tablet layer contains, based on the weight of each tablet layer, up to 5% permeable agent, up to 5% antistatic agent, up to 20% water-insoluble diluent, up to 15% agent.

Binder, up to 2.6% sweetener, up to 1.3% flavor, up to 0.5% colorant. At least one active ingredient is in a modified release form. At least one active ingredient is in crystalline form, or in the form of a core containing a taste-masking coating.

The present invention relates to a process for preparing a tablet comprising the following steps;

1. producing at least two types of optionally coated active substance particles;

2. preparation of at least two dry mixtures, each containing tabletting excipients and at least one type of active ingredient particles;

3. pre-pressing at least one of the above-obtained powder mixture with a pressing force of 0.5 to 15 kN;

4. applying the other mixture prepared in Step 2 to the above mixture;

5. optionally pre-pressing the mixture obtained in step 4, with a pressing force ranging from 0.5 to 15 kN;

6. final compression of the pre-formed layers obtained above, with a compression force in the range of 5 to 50 kN, where steps 4 and 5 may optionally be repeated at least once depending on the number of layers of the tablet.

The number of layers is limited by the thickness of the tablet, which must be acceptable to the patient, and generally does not exceed three layers.

In a first embodiment of the invention, the orodispersible tablet is a two-layered tablet containing at least one active substance in each layer.

In a first embodiment of the invention, the orodispersible tablet is a three-layer tablet.

In the latter case, the three layers may contain the active substance or one of the layers may contain only an excipient.

Preferably, an excipient-only layer is sandwiched between two layers containing at least one active ingredient.

According to one variant of the invention, the active substance of the two layers is the same basic molecule, but the substance molecule in one of the layers may differ from the molecule present in the other layer, the type of salt or base used, or the crystalline polymorphic or amorphous state, and / or the solubility and / or pharmacokinetic characteristics of the molecule.

According to another variant of the invention, the active substance present in each of the layers is chemically identical, but is formed differently in each of the layers, having significantly different release rates in vitro and in vivo.

The active substance is, for example, in the form of particles with modified properties such that an effective release of the substance takes place over a period of between 8 and 24 hours, or with delayed release properties that allow the substance to be released at a specific absorption site or to avoid degradation in an unfavorable pH environment.

According to this embodiment of the invention, the active substance of the other layer is in an intermediate form, optionally coated if the particle requires taste masking, or is modified to a different profile from the active substance of the first layer.

Taste releasing or masking characteristics can be achieved by known methods, but preferably by coating the active substance particle with polymers.

The plasma characteristics obtained by administering the tablet to the patient show several plasma concentration peaks, corresponding to different rates of release of particles from each layer. These particles are swallowed simultaneously after the orodispersible tablet has disintegrated.

The active substance (s) may be selected from any family of drugs, for example gastrointestinal sedatives, antacids, analgesics, anti-inflammatory agents, coronary vasodilators, peripheral and cerebral vasodilators, anti-inflammatory agents. infections, antibiotics, anti-viral agents, anti-parasitic agents, anti-cancer agents, anti-anxiety agents, neuroleptics, central nervous system stimulants, anti-depressants, antihistamines, anti-diarrheal agents, laxatives, additives dietetic, immuno depressants, blood cholesterol lowering agents, hormones, enzymes, anti-convulsants, anti-anginal agents, heart rate medical products, antihypertensive medical products, anti-migraine drugs, anti-migraine products medical drugs that act on blood clotting, antiepileptics, relaxing agents muscles, medical products used to treat diabetes,

Medical products used to treat thyroid disorders, diuretics, anorexic agents, anti-asthmatic agents, expectorants, anti-cough agents, mucus regulating agents, decongestants, hypnotics, hematopoietic agents, uric acid-secreting agents, plant extracts, contrast agents, or compounds from another family of drugs, combinations of active substances possibly selected from the same family or from different families.

The active substances can be in the form of pharmaceutically acceptable salts thereof or in polymorphic form (racemic mixtures, enantiomers, etc.). The phrase "pharmaceutically acceptable salts" means derivatives of these compounds wherein the base form of the pharmaceutically acceptable compound is converted to a base or acid salt. Examples of pharmaceutically acceptable salts include especially salts of organic acids or mineral acids, or basic residues such as amines; alkali derivatives or organic salts of acidic residues such as carboxylic acids and the like. Pharmaceutically acceptable salts include standard non-toxic salts or quaternary ammonium salts of a basic compound, formed, for example, from non-toxic mineral or organic acids. For example, such standard non-toxic salts include derivatives of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and the like; salts made from organic acids such as amino acids, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamic acid, maleic acid, hydroxymaleic acid, acid phenylacetic acid, glutaamic acid, benzoic acid, salicylic acid, sulfanilic acid, 1-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isothionic acid, and the like.

The pharmaceutically acceptable salts of the invention can be prepared by synthesizing an essentially therapeutic compound containing an acidic or basic fraction by standard methods. Generally, such salts can be prepared by reacting the free acid or free base with a predetermined amount of the appropriate base or acid in water or an organic solvent, or in a mixture of water and an organic solvent.

Non-aqueous environments are preferred. For a list of suitable salts, see Remington's Pharmaceutical Science, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p. 1418.

The phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or pharmaceutical forms which, medically acceptable, are suitable for use in contact with human or animal tissue without causing toxicity, irritation, allergy or other undue hassle or complication. in relation to the profit / risk ratio.

The multilayer orodispersible tablet according to the invention is particularly suitable for administering medicinal products in combination as it makes it possible both to reduce the daily amount of units administered to a patient and to improve the patient's treatment fit in the case of individual swallowing difficulties.

The combinations are tested, especially in pharmaceutical laboratories, the following combinations are not intended to be limiting thereto.

Combinations of active substances are useful, especially in the field of analgesics, when synergistic effects are indicated and needed, for example the combination of morphine, oxycodone, hydrocodone or tramadol with a second analgesic such as ibuprofen paracetamol, or in the field of anti-inflammatory agents by combining ketoprofen with naproxen , or diclofenac with misoprostol.

It is also possible to co-administer an opiate analgesic, for example oxycodone or morphine, with an opiate receptor antagonist such as naloxone or naltrexone in order to avoid the misuse of medicinal products by drug addicts.

In the anti-ulcer art, preferred combinations include combinations of anti-ulcer agents, for example a proton pump inhibitor such as omeprazole, an H-2 receptor inhibitor such as famotidine or ranitidine, or an antacid.

In the field of cholesterol-lowering and anti-diabetic agents, combinations of particles belonging to different chemical families are possible, including fibrates, for example fenofibrate, biguanidinyl such as metformin, or statins such as atorvastatin or simvastatin.

In other fields, research is also carried out on combinations, especially with medicinal products, which are effective in the treatment of the AIDS virus or as anti-cancer agents.

PL 211 301 B1

The active substances, the particle size of which is between 20 μm and 1000 μm, may be in the form of a powder or microcrystals, or in the form of granules obtained by dry, wet or warm granulation, or alternatively in the form of granules obtained by depositing on a neutral substrate, or by extrusion-spheronization.

As used herein, the term "active moiety" means those forms in which the active substances can be used.

The active substance, initially in the form of a powder or microcrystals, is used in dry form for granulation and in the form of a solution or suspension in an aqueous or organic solvent to be deposited on an inert support.

The inert support may consist of a chemically or pharmaceutically inert excipient, existing in particulate, crystal or amorphous form, for example sugar derivatives such as lactose, sucrose, hydrolyzed starch (maltodextrin) or cellulose.

Mixtures of agents such as sucrose and starch, or cellulose based mixtures, can also be used to prepare spherical inert substrates.

The unit particle size on the inert support is in the range from 50 nm to 500 nm, preferably 90 nm to 150 nm.

The active particles may also include one or more excipients selected from the group consisting of binders, diluents, antistatic agents, micro-pH modifiers, and mixtures thereof.

The binder constitutes up to 15% by weight, preferably up to 10% by weight based on the weight of the uncoated particles, and may be selected from the group consisting especially of cellulose-based polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch , pregelatinized starch, sucrose and mixtures thereof, guar gum, polyethylene glycols, and mixtures thereof.

The diluent constitutes up to 95% by weight, preferably up to 50% by weight with respect to the weight of the uncoated particles, and may be selected from the group consisting of, especially cellulose-based derivatives, preferably microcrystalline cellulose, polyols, preferably mannitol, starch, sugar derivatives such as lactose , and mixtures thereof.

The antistatic agent is present in an amount of up to 10 wt.%, Preferably up to 3 wt.% Based on the weight of the uncoated particles, and may be selected from the group consisting especially of colloidal silica, especially the product sold under the name Aerosil®, preferably precipitated silica, especially the product sold under the name Syloid®, FP244, micronized and non-micronized talc, and mixtures thereof.

The micro-pH modifying agent can be an acidic or basic compound.

The acidic agent can be any mineral or organic acid in the form of the free acid, acid anhydride or acid salt.

The above acid is selected from the group consisting especially of tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, α-hydroxy acids, ascorbic acid, and amino acids, and also salts and derivatives of these acids.

The basic compound is selected from the group consisting of potassium, lithium, sodium, calcium or ammonium carbonate, or L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium amino acid carbonates, anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, and mixtures thereof. In the context of the present invention, the term carbonate is understood to mean either carbonate, sesquicarbonate or bicarbonate.

The amount of modifying agent surrounding the micro-pH ranges from 0.5% to 20%, preferably from 5 to 15%, more preferably from 5 to 10%, based on the weight of the uncoated particles.

When desired, the powder, microcrystals or particles of the active ingredient may advantageously be coated with a layer of the composition with a particular desired selected trait, especially taste masking and / or modifying or retarding or sustaining drug release.

The coating composition is selected on the basis of the physicochemical characteristics of each active substance and consists of at least one coating polymer.

PL 211 301 B1

The coating polymer may be insoluble or soluble only at certain pH levels, and is preferably selected from the group consisting of cellulose-based polymers, acrylic polymers, and vinyl polymers, and mixtures thereof.

Among the cellulose based polymers, preferred will be those selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate cellulose succinate, cellulose cellulose acetate methyl acetate methyl cellulose carboxymethyl cellulose as such or as mixtures.

Among the acrylic polymers, those selected from the group consisting of ammonium methacrylate copolymer (Eudragit® RL and RS), polyacrylate (Eudragit® NE) and polymethacrylate (Eudragit® E), methacrylic acid copolymer sold under the trade name Eudragit® L100 or Eudragit® will be preferred. L30D, Eudragit® is the filename applied by Rohm.

Other polymers may also be used, for example shellac, polyvinyl acetate phthalate, or the other polymers as such or in admixture or separately combined.

The coating composition is preferably applied by spraying a solution, suspension or colloidal dispersion and coating polymer in a solvent or mixture of solvents to form a continuous film coating completely the surface of each particle, regardless of the surface condition, in an amount sufficient to, for example, mask the taste at the point in time. administering the medicinal product while the coated particles remain in the mouth.

The thickness of the film is generally between 5 µm and 75 µm, usually depending on the solubility of the active ingredient at the saliva pH and more or less on the nature of the bitterness taste.

The polymer is applied to the surface of the active substance particles in an amount of up to 60%, preferably up to 20% by weight. based on the weight of the coated particles.

The solvent for spraying the coating polymer is selected from the group consisting of water, an organic solvent such as ethanol, isopropanol, acetone or methylene chloride, or a mixture of solvents.

The coating composition may also contain a surfactant, plasticizer, antistatic and / or glidant.

The plasticizer is used in an amount of not more than 40%, preferably between 15% and 30% by weight, based on the dry weight of the polymer. It is selected from the group consisting of triethyl citrate, acetyl tributyl citrate, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, monoacetylated and diacetylated glycerides, and mixtures thereof.

The surfactant is selected from the group consisting of anionic, cationic, nonionic and amphoteric surfactants.

The antistatic agent is used in an amount of not more than 10% by weight, preferably between 0 and 3%, more preferably less than 1% by weight, based on the dry weight of the polymer. It is selected from the group consisting of micronized or non-micronized talc, colloidal silica (Aerosil® 200), treated silica (Aerosil® R972), or precipitated silica (Syloid® FP244), and mixtures thereof.

The lubricant is used in an amount of not more than 10% by weight, preferably between 0 and 3%, more preferably less than 1% by weight, based on the dry weight of the polymer. It is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols, sodium benzoate, and mixtures thereof.

The size of the coated particle typically ranges from 50 µm to 1000 µm, preferably from 100 µm to 800 µm, more preferably from 200 µm to 500 µm, and is determined by conventional methods, for example using calibrated mesh size screens, or a spreading laser.

The particle size distribution of the coated particles typically determined by one of the above methods is such that at least 80% by weight of the population of coated particles has a size ranging from 90 µm to 500 µm, preferably from 150 µm to 500 µm, and the D50% value is from 200 µm to 400 um.

The mixture of excipients present in each tablet layer sometimes refers herein to the expression tabletting excipients, as opposed to the excipients used to form the particles of the active substance.

The mixture necessarily contains at least one dissolving agent, at least one disintegrant and / or at least one swelling agent.

PL 211 301 B1

The dissolving agent is selected from the group consisting of sugars such as sucrose, lactose, fructose, dextrose, or polyols containing less than 13 carbon atoms such as mannitol, xylitol, sorbitol, maltitol, lactitol or erythritol, as such or in admixture.

The dissolving agent is used in an amount of from 20% to 90% by weight, preferably from 30% to 60% by weight, based on the weight of each layer of the tablet.

The dissolving agent is used in compressible form, the primary particle diameter is in the range 100 μm to 500 μm, or in the form of a powder where the primary particle diameter is below 100 μm, said powder is used as such or as a mixture with the primary particle. compress the product.

Each tablet layer may contain a single dissolving agent or a mixture of at least two dissolving agents. The dissolving agent may be used, as the case may be, either in compressible form or in non-compressible powder form.

The tablet may contain the same dissolving agent in each layer or the same mixture of dissolving agents but different in each layer, not only with regard to the nature of the dissolving agent but also with regard to the particle size and, in the case of a mixture, to the ratio of their fractions to each other. .

In a first preferred embodiment of the invention, each tablet layer contains the same dissolving agent in compressible form.

In a second preferred embodiment of the invention, each tablet layer comprises a mixture comprising a compressible dissolution agent and the same powder dissolving agent in a compressible to powder ratio of between 99/1 and 20/80.

In a third preferred embodiment of the invention, the tablet comprises the same dissolving agent or the same mixture of dissolving agents in each layer of the tablet.

The disintegrant is selected from the group consisting, in particular, of cross-linked sodium carboxymethylcellulose, known in the art as croscarmellose, cross-linked polyvinylpyrrolidone, known in the art as crospovidone, and mixtures thereof.

The disintegrant is present in an amount of from 1% to 20% by weight, preferably from 5% to 15% by weight, in the case of a mixture, each disintegrant is present in an amount from 0.5% to 15% by weight, preferably from 5% by weight. up to 10% by weight, calculated on the weight of each tablet layer.

The swelling agent is selected from the group consisting of microcrystalline cellulose, starch, a modified starch such as carboxymethyl starch or sodium glycol starch, alginic acid or sodium alginate, or mixtures thereof.

The swelling agent is present in an amount of from 1% to 15% by weight, based on the weight of each tablet layer.

In addition to the excipients mentioned above, each layer of the orodispersible tablet of the invention may optionally contain a lubricant, a permeable agent, an antistatic agent, a water-insoluble diluent, a binder, a sweetener, a flavoring agent, a colorant and adjuvants.

The lubricant is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols, sodium benzoate, pharmaceutically acceptable oils, preferably dimethicone or liquid paraffin, or mixtures thereof.

The lubricant is present in an amount of up to 2% by weight, preferably from 0.5% to 1% by weight, calculated on the weight of each tablet layer.

In the first embodiment of the invention, the lubricant is completely incorporated in the mixture of the tabletted excipient. In the second variant of the invention, the lubricant is sprayed onto the die and the punch during pressing, the fraction of said lubricant in the form of a powder or a liquid.

The amount of lubricant used in the inner and / or outer phase is carefully selected to prevent the reverse effect of layer cohesion during the primary compression of the tablet.

The permeable agent is selected from the group consisting, in particular, of silica with a high affinity for aqueous solvents such as precipitated silica, commonly known under the trade name Syloid®, maltodextrin, and β-cyclodextrin, and mixtures thereof.

PL 211 301 B1

The permeable agent is present in an amount of up to 5% by weight, calculated on the weight of each tablet layer.

The antistatic agent may be selected from the group consisting of micronized or non-micronized talc, colloidal silica (Aerosil® 200), treated silica (Aerosil® R972), or precipitated silica (Syloid® FP244), and mixtures thereof.

An antistatic agent is present in an amount of up to 5% by weight, calculated on the weight of each tablet layer.

The water-insoluble diluent is selected from the group consisting of dicalcium phosphate, tricalcium phosphate, and microcrystalline cellulose.

Its role is to improve the disintegration process by increasing the insoluble charge of the tablet. It is used in an amount of up to 20% by weight, preferably less than 10% by weight, based on the weight of each tablet layer.

The binder is used in dry form and may be starch, sugar, polyvinylpyrrolidone, or carboxymethylcellulose as such or in admixture.

It is preferably used in only one layer of the tablet, and in an amount of up to 15% by weight, preferably less than 10% by weight, based on the weight of the layer in which it is present.

The sweetener is selected from the group consisting especially of aspartame, potassium acetylsulfame, sodium saccharin, neohesperidin dihydrochalcone, sucrose and monoammonium glycyrrhizinate, and mixtures thereof.

Flavoring and coloring agents are used as pharmaceuticals in conventional tablet manufacture.

In one particularly preferred embodiment of the invention, each layer has a color different from that of the adjacent layer so that the tablet layer structure is immediately visible.

Adjuvants can also be added to the tablet formulation and are selected from the group consisting of a disintegrant, for example amino acids or proteins, pH adjusting agents, disrupting systems, especially carbon dioxide generators of the type of pH adjusting agents used, or surfactants. open.

In the layer containing the pharmaceutically active substance, the amount of the mixture of excipients in relation to the coated or uncoated active substance is from 0.4 to 10, preferably from 1 to 5 parts by weight.

According to a preferred embodiment of the invention, each tablet layer contains the same excipients so that the disintegration of the tablet in the mouth produces the same feeling as the disintegration of a dispersible monolayer tablet with the same qualitative composition. The patient does not feel any difference in the degree of degradation between the different layers of the tablet.

The quantitative composition of each layer is adapted to the content of each active substance.

The maximum mass ratio between the thickness and the thinness of the layer is 10/1.

In the case where the ratio between the heaviest dose of active ingredient and the lightest dose of active ingredient is greater than 10, the amount of diluent is adjusted such that the weight ratio between the layers is the reciprocal of 10. In this case, the diluent is preferably a soluble agent, more preferably a soluble agent in a compressible form.

The tablets range in diameter from 6 mm to 18 mm.

The tablets may be round, oval or oblong in shape, they may have a flat, concave or optionally engraved surface.

The stamps are preferably biconvex or biconcave in shape.

Tablets generally weigh from 0.1 grams to 2.0 grams. The invention also relates to a process for the preparation of the above-described multi-layer tablets.

The method according to the invention comprises the following steps;

1. producing at least two types of optionally coated active ingredient particles;

2. preparation of at least two dry mixtures, each containing tableting excipients and at least one type of active substance particles;

3. pre-compressing at least one of the above obtained powder mixture;

4. applying a different mixture to the above mixture;

5. possible pre-ironing;

6. finally pressing the pre-formed layers obtained above;

steps 4 and 5 may be repeated at least once depending on the number of layers of the tablet.

PL 211 301 B1

In the case of a two-layered tablet, the production method according to the invention comprises the following steps;

- preparation of two types of optionally coated active substance particles;

- preparation of two dry mixtures, each containing completely tableting excipients and at least one type of active substance particles;

- pre-compression of one of the mixtures obtained above, as a preliminary formulation of the lower layer of the tablet,

- using the second mixture to preform the layer;

- optionally pre-compressing the second mixture to obtain a top tablet layer;

- final ironing.

In the case of a three-layer tablet, the manufacturing process according to the invention comprises the following steps;

- producing at least two types of optionally coated active substance particles;

- preparation of three dry mixtures, each containing tableting excipients and at least two types of active substance particles;

- pre-compression of one of the mixtures obtained above, as a preliminary formulation of the lower layer of the tablet,

- using the second mixture to preform the layer;

- pre-compressing the second mixture to obtain a middle tablet layer;

- using a third mixture to form the layer;

- optionally pre-compressing the third mixture to form a bottom tablet layer;

- final ironing.

In a preferred embodiment of the invention, the preparation of each mixture comprises two steps, a first step consisting of mixing the uncoated active substance with all tableting excipients except for the lubricant inward, and a second step involving wholly or partially adding the lubricant to the first mixture, the remainder of the agent is sprayed onto the punch and / or the inner surface of the die.

In the event that all of the lubricant is sprayed onto the punch and / or the inner surface of the die, a second mixing step is obviously unnecessary.

Pre-compression and main compression steps performed on a rotary or impact tablet press.

The precompression step aims, on the one hand, to precompress the layer by filling the matrix with the powder mass and then removing gas from the powder mass by shifting the particles so as to avoid separation during the main compression. Separation of substances can occur either between the layers due to lack of adhesion or in the layer itself.

In a tablet in which the layers do not have the same relative weight and / or thickness size, the first layer formulated is the one that has the greater weight or thickness.

The pressure applied during pre-pressing is between 0.5 and 15 kN and is generally 5-10 times lower than the pressure applied during the main (final) pressing.

The pressure during the main pressing step is from 5 to 50 kN, preferably from 5 to 15 kN.

During pre-pressing, the compressive forces applied to the powder mass are adjusted to two possible operating modes. The first mode includes adjusting the pressing forces to the weight of the powder mass in the die, the second mode is a function of the powder volume versus the pressure force, and the die adjusts the volume filled with the powder from the pressure exerted by the punch.

Tablet hardness is preferably from 1 to 10 kp, more preferably from 1 to 6 kp as determined by the method of European Pharmacopoeia (2.9.8), 1 kp is the equivalent of 9.8 N.

The hardness of the multilayer tablet is adjusted so as to obtain a suitable friability as measured by the European Pharmacopoeia method of less than 2%, preferably less than 1%. Good friability allows the tablet to disintegrate in the mouth under the action of saliva to be less than or equal to 60 seconds, preferably less than or equal to 40 seconds.

In the case where the tablet of the invention contains the active ingredient in a coated form, either for masking an unpleasant taste or for delaying or sustaining release of the substance, pressure must be applied so as to maintain an identical solubility profile between the particles of the coated material before and after compression. The term "identical

PL 211 301 B1 means that the difference in the degree of active ingredient release in vitro, in each individual step, must not be greater than 15% of the total value.

The invention will be better understood from the tablet preparation examples which are only illustrative of the invention and are not intended to limit the protection scope thereto only.

Excipients used

Compressible Mannitol M 300; Parteck® sold by Merck;

Mannitol 60 powder; Pearlitol® 160C marketed by the company Roquette Freres;

Crospovidone; Killidon® CL marketed by BASF;

Saccharose; sold by the McNeill Company;

Aspartame; sold by the NutraSweet company; Rootbeer Mint and Vanilla Biscuit; marketed by the company Pharmarome;

Magnesium stearate; sold by the company Peter Graven.

Equipment

60L or 200L mixer with Soneco or BSI two-blade mixer.

The tablet press used in Example 1, 2 and 3, Courtoy R29F equipped with 55 B stations of which only 28 are used.

The tablet press includes a 2-feed system and can be used in a 2-spout mode when compressing high-strength single-layer tablets, or in a 1-spout mode when compressing two-layer tablets.

The tablet press used in Example 4 and 5, the Fette PT3090, is equipped with 61 B stations and 49 D stations.

P r z k ł a d 1

Orally dispersible two-layer tablet containing 500 mg paracetamol (acetaminophen) and 65 mg caffeine

1 / Mixtures

The first powder mixture (layer A) is prepared according to the formulation formula in Table 1.

T a b e l a 1

Composition (% w / w) Coated paracetamol 46.9% Mannitol M300 21.5% Mannitol 60 21.5% Kollidon CL 6.9% Saccharose 1.0% Rootbeer mint flavor 1.0% Vanilla Biscuit flavor 0.2% Magnesium stearate 1.0% Whole 100.0%

Coated paracetamol particles were produced by granulating or coating in an air fluidized bed. The particle size distribution of said particles was determined by laser diffraction and is such that 98% by weight of the coated particles have a size between 150 and 500 nm.

The flavored premix comprising Mannitol 60, Kollidon CL, sucrose and flavorings is prepared by blending the various ingredients in the proportions given in Table 1 for 15 minutes at 10 rpm.

Mannitol M300 and coated paracetamol granules were added to the first mixture in the proportions given in Table 1. Mixing time 20 minutes at 10 rpm.

The lubricant (lubrication step) was added to the resulting mixture for 2 minutes at a speed of 10 rpm.

The second mixture, comprising the coated caffeine and the tableting excipients listed in Table 2, was prepared according to the same procedure as reported for the first mixture.

PL 211 301 B1

T a b e l a 2

Composition (% w / w) Coated caffeine 42.3% Mannitol M300 23.2% Mannitol 60 23.2% Kollidon CL 7.4% Saccharose 1.1% Rootbeer mint flavor 1.1% Vanilla Biscuit flavor 0.2% Green dye 0.5% Magnesium stearate 1.0% Whole 100.0%

Coated caffeine particles were prepared by granulating or coating in an air fluidized bed. The particle size distribution of said particles is determined by laser diffraction and is such that 98% by weight of the coated particles have a size between 150 and 500 Pm.

2 / Ironing

The tablet press is a Courtoy R29F compression device equipped with 55 B-stations, of which only 28 are used.

The first layer A (1200 mg weight) is formulated with an initial pressure of 4.8 kN, the thickness is determined by a weight of 1200 mg.

Mixture B (weight 200 mg) was applied to the surface of the first layer A in the matrix. An initial pressure of 2.3 kN was applied, before the main pressing of the two gradually formed layers under a force of 15.3 kN, until the tablet hardness of 50 - 60 N was obtained.

Round, flat and chamfered punches with a diameter of 16.5 mm were used.

Double-layered tablets with a theoretical weight of 1400 mg, containing a dose of 500 mg of paracetamol and 65 mg of caffeine, were produced.

The final composition of each tablet was as follows;

T a b e l a 3

Unit composition (mg) Layer A 1 2 Coated paracetamol 563.5 Mannitol M300 257.6 Mannitol 60 257.6 Kollidon CL 82.6 Saccharose 12.6 Rootbeer mint flavor 11.8 Vanilla Biscuit flavor 2.4 Magnesium stearate 11.9 Total weight of layer A 1,200.00 Layer B Coated caffeine 84.6 Mannitol M300 46.4

PL 211 301 B1 cont. table 3

1 2 Mannitol 60 46.4 Kollidon CL 14.8 Saccharose 2.3 Rootbeer mint flavor 2.1 Vanilla Biscuit flavor 0.4 Green dye 1.0 Magnesium stearate 2.0 Total weight of layer B 200.00 The total weight of the tablet 1,400.00

The tablets thus obtained had the physical and chemical characteristics shown in Table 4.

T a b e l a 4

Measure (CV) Weight (mg) (n = 16) 1,400.1 (2.7%) Hardness (N) (n = 10) 44.7 (16.3%) Oral disintegration (n = 6) Min; 20s max; 3 5 p

P r z k ł a d 2

Orally dispersible bilayer tablet containing 325 mg paracetamol (acetaminophen) and 37.5 mg tramadol hydrochloride (HCl tramadol)

A batch of 14,000 tablets was prepared as follows.

1 / Mixture

All mixtures were prepared according to the procedure given in Example 1. The first mixture (layer A, weight 800 mg) consisted of paracetamol coated with 20% (based on the weight of dry coating polymer relative to the weight of the coated particles) with a polymer blend of Eudragit® E100 / Eudragit® NE30D in the ratio 67/33, and tableting excipients in the proportions given in table 5.

T a b e l a 5

Composition (% w / w) Coated paracetamol 46.0% Mannitol M300 20.6% Mannitol 60 20.6% Kollidon CL 9.4% Aspartame 1.9% Rootbeer mint flavor 0.9% Magnesium stearate 0.6% Whole 100.0%

The second mixture (layer B, weight 800 mg) contained tramadol hydrochloride coated with 35% (based on the weight of dry coating polymer relative to the weight of the coated particles) with ethylcellulose N7, and tableting excipients in the proportions given in Table 6.

Coated tramadol particles were produced by granulation or coating in an air fluidized bed. The particle size distribution of said particles was determined by laser diffraction and was as follows;

The D10%, D50%, and D90% values were 187 nm, 330 nm, and 530 nm, respectively.

PL 211 301 B1

T a b e l a 6

Composition (% w / w) Coated with tramadol HCl 28.3 Mannitol M300 27.3 Mannitol 60 27.3 Kollidon CL 12.4 Aspartame 2.5% Rootbeer mint flavor 1.2 Green dye 0.5% Magnesium stearate 0.5% Whole 100.0%

2 / Ironing

The compression was performed using equipment as set out in Example 1.

Theoretically, each tablet contained 325 mg paracetamol and 37.5 mg tramadol HCl. The tablet press was equipped with round, flat and chamfered punches with a diameter of 15 mm. The first layer A (800 mg weight) was poured under an initial pressure of 1.6 kN.

Mixture B (weight 200 mg) was applied to the surface of the first layer A in the matrix.

An initial pressure of 0.8 kN was applied, before the main pressing of the two gradually formed layers, under a force of 10 kN, until the tablet hardness was 50 N.

In the above batch of 14,000 tablets, each tablet had the composition shown in Table 7.

T a b e l a 7

Unit composition (mg) Layer A Coated paracetamol 367.7 Mannitol M300 165.0 Mannitol 60 165.0 Kollidon CL 75.2 Aspartame 15.0 Rootbeer mint flavor 7.5 Magnesium stearate 4.6 Total weight of layer A 800.00 Layer B Coated with tramadol HCl 56.6 Mannitol M300 54.6 Mannitol 60 54.6 Kollidon CL 24.7 Aspartame 5.0 Rootbeer mint flavor 2.5 Green dye 1.0 Magnesium stearate 1.0 Total weight of layer B 200.00 The total weight of the tablet 1,000.00

PL 211 301 B1

The tablets thus obtained had the physical and chemical characteristics shown in Table 8.

T a b e l a 8

Measure (CV) Weight (mg) 1005.1 (n = 16) (0.42%) Hardness (N) 40.7 (n = 10) (5.6%) In vitro disintegration Min; 12 pp (n = 6) Max; 35 pp Oral disintegration (n = 3) 20 - 35 pp Paracetamol content 326.7 (n = 3) (0.9%) Tramadol content 41.7 (n = 3) (1.6%)

P r z k ł a d 3

Orally dispersible bilayer tablet containing 200 mg ibuprofen and 37.5 mg tramadol hydrochloride (HCl tramadol)

A batch of 14,000 tablets was obtained as follows.

1 / Mixtures

All mixtures were prepared according to the procedure described in Example 1. Coated ibuprofen particles were prepared by granulating or coating in an air fluidized bed. The particle size distribution of said particles was determined by laser diffraction and was as follows;

The D value of ₅₅ % was 258 µm, 2% by weight of the particles were less than 90 µm, and 1% by weight of the particles were larger than 500 µm.

98% by weight of the coated particles have a size between 150 and 500 µm.

The first mixture (layer A) contained ibuprofen coated with 13.7% (based on the weight of dry coating with respect to the weight of the coated particles) with ethylcellulose N7, and tableting excipients in the proportions given in Table 9.

T a b e l a 9

Composition (% w / w) Coated with ibuprofen 32.0 Mannitol M300 20.7 Mannitol 60 20.7 Kollidon CL 9.9 Aspartame 2.5 Rootbeer mint flavor 1.0% Magnesium stearate 0.6% Whole 100.0%

The second mixture (layer B) contained tramadol hydrochloride coated with 35% (by dry weight) of the coating polymer by weight of the coated particles with ethylcellulose N7, and tableting excipients in the proportions given in Table 10. The coated tramadol particles had characteristics identical to the particles from example 2.

PL 211 301 B1

T a b e l a 10

Composition (% w / w Coated with tramadol HCl 28.3 Mannitol M300 28.4 Mannitol 60 28.4 Kollidon CL 10.4 Aspartame 2.6 Rootbeer mint flavor 1.0 Green dye 0.5 Magnesium stearate 0.4 Total weight 200.00

2 / Ironing

Theoretically, each tablet contained 200 mg of ibuprofen and 37.5 mg of tramadol HCl.

The tablet press was equipped with round, flat and chamfered punches with a diameter of 15 mm.

The first layer A (800 mg weight) was poured under an initial pressure of 1.6 kN.

The mixture of layer B (weight 200 mg) was applied to the surface of the first layer A in the matrix.

An initial pressure of 0.8 kN was applied, before essentially compressing the two layers gradually formed under a force of 10-12 kN to a tablet hardness of 50 N. Each tablet had the composition shown in Table 11.

T a b e l a 11

Unit composition (mg) Layer A Coated with ibuprofen 255.6 Mannitol M300 216.4 Mannitol 60 216.4 Kollidon CL 79.1 Aspartame 19.8 Rootbeer mint flavor 7.9 Magnesium stearate 4.8 Total weight of layer A 800.00 Layer B Coated with tramadol HCl 56.6 Mannitol M300 56.78 Mannitol 60 56.78 Kollidon CL 20.76 Aspartame 5.18 Rootbeer mint flavor 2.08 Green dye 1.00 Magnesium stearate 0.84 Total weight of layer B 200.00 The total weight of the tablet 1,000.00

The tablets thus obtained had the physical and chemical characteristics shown in Table 12.

PL 211 301 B1

T a b e l a 12

Measure (CV) Weight (mg) 998.5 (n = 16) (0.4%) Hardness (N) 50.9 (n = 10) (8.0) In vitro disintegration Min; 14 pp (n = 6) Max; 20 s Disintegration in the mouth (n = 3) 20 - 35 pp Ibuprofen content 205.1 (n = 3) (0.6%) Tramadol content 38.3 (n = 3) (0.3%)

P r z k ł a d 4

Orally dispersible two-layer tablet containing 500 mg paracetamol and 65 mg caffeine

1 / Mixtures

The first powder mixture (layer A) is made according to the formulation formulation in Table 13.

T a b e l a 13

Composition (% w / w) Coated paracetamol 47.2% Mannitol M300 21.6% Mannitol 60 21.6% Kollidon CL 6.9% Saccharose 1.0% Rootbeer mint flavor 1.0% Vanilla Biscuit flavor 0.2% Magnesium stearate 0.4% Whole 100.0%

A second mixture comprising coated caffeine and tableting excipients listed in Table 14.

T a b e l a 14

Composition (% w / w) Coated caffeine 42.5% Mannitol M300 23.3% Mannitol 60 23.3% Kollidon CL 7.5% Saccharose 1.2% Rootbeer mint flavor 1.1% Vanilla Biscuit flavor 0.2% Green dye 0.5% Magnesium stearate 0.4% Whole 100.0%

PL 211 301 B1

Both mixtures were prepared according to the same procedure as in Example 1.

The coated paracetamol particles and the coated caffeine particles had the same granulation characteristics as given in Example 1.

2 / Compression stations (from 49 die stations of the Fette PT 3090 tablet press) were equipped with round, biconcave punches with a diameter of 17 mm.

An external lubricant, magnesium stearate, was used to lubricate the punches and dies.

The first layer A (1800 mg weight) is formed under an initial pressure of 2.2 kN, the thickness is determined by a weight of 1200 mg.

Mixture B (weight 200 mg) was applied to the surface of the first layer A in the matrix. An initial pressure of 11.2 kN was applied, before the main pressing of the two gradually formed layers, under a force of 15.3 kN, until the tablet hardness was 70 N.

89,438 tablets were prepared at a maximum tabletting speed of 80,000 tablets / hour.

The produced double-layered tablets with a theoretical weight of 1400 mg contained a dose of 500 mg of paracetamol and 65 mg of caffeine.

The final composition of each tablet is shown in Table 15;

T a b e l a 15

Unit composition (mg) Layer A Coated paracetamol 556.9 Mannitol M300 259.2 Mannitol 60 259.2 Kollidon CL 83.0 Saccharose 12.7 Rootbeer mint flavor 11.9 Vanilla Biscuit flavor 2.4 Magnesium stearate 4.7 Total weight of layer A 1,200.00 Layer B Coated caffeine 84.6 Mannitol M300 46.4 Mannitol 60 46.4 Kollidon CL 14.8 Saccharose 2.3 Rootbeer mint flavor 2.1 Vanilla Biscuit flavor 0.4 Green dye 1.0 Magnesium stearate 2.0 Total weight of layer B 200.00 The total weight of the tablet 1,400.00

The tablets thus obtained had the physical and chemical characteristics shown in Table 16.

PL 211 301 B1

T a b e l a 16

Measure (CV) Weight (mg) 1390.2 (n = 20) (1.9%) Hardness (N) 70.7 (n = 10) (5.4%) Disintegration in the mouth (n = 6) 30 s

P r z k ł a d 5

Orally dispersible bilayer tablet containing 325 mg paracetamol and 37.5 mg tramadol hydrochloride (HCl tramadol)

1 / Mixtures

All mixtures were prepared according to the first step of Example 2.

The coated paracetamol particles and the coated tramadol particles had the same grain distribution characteristics as reported in Example 2.

Round, convex punches (radius 25 mm) with a diameter of 16 mm were used.

The Fette PT 3090 tablet press was equipped with 61 round, convex (25 mm radius) punches with a diameter of 16 mm.

An external lubricant, magnesium stearate, was used to lubricate the punches and dies.

The first layer A (weight 800 mg) is formed under an initial pressure of 2.3 kN. Mixture B (weight 200 mg) was applied to the surface of the first layer A in the matrix. An initial pressure of 13 kN was applied, before the main pressing of the two gradually formed layers, under a force of 37.1 kN, until a tablet hardness of 50 N was obtained.

93,777 tablets were prepared at maximum speed and with a tabletting of 110,000 tablets / hour.

The produced double-layered tablets with theoretical weight of 1000 mg contained a dose of 325 mg of paracetamol 137.5 HCl tramadol.

The final composition of each tablet is shown in Table 17;

T a b e l a 17

Unit composition (mg) Layer A 1 2 Coated paracetamol 368.5 Mannitol M300 164.5 Mannitol 60 164.5 Kollidon CL 75.2 Aspartame 15.0 Rootbeer mint flavor 7.5 Magnesium stearate 4.8 Total weight of layer A 800.00 Layer B Coated with tramadol HCl 56.6 Mannitol M300 54.6 Mannitol 60 54.6 Kollidon CL 24.7

PL 211 301 B1 cont. table 17

1 2 Aspartame 5.0 Rootbeer mint flavor 2.5 Green dye 1.0 Magnesium stearate 1.0 Total weight of layer B 200.00 The total weight of the tablet 1,000.00

The tablets thus obtained had the physical and chemical characteristics shown in Table 18.

T a b e l a 18

Measure (CV) Weight (mg) 991.4 (n = 20) (0.6%) Hardness (N) 51.7 (n = 10) (5.8%) Brittleness (%) (n = 10) 0.06 Oral disintegration (n = 6) 20 s

Patent claims

Claims (7)

A tablet with at least two superimposed and integral layers, two of the layers containing at least one active substance, characterized in that each of these layers comprises a mixture of excipients comprising, based on the weight of each tablet layer; - 20 to 90% at least one soluble agent selected from the group consisting of sugars, polyols with less than 13 carbon atoms, and mixtures thereof; - 1 to 20% at least one tablet disintegrant; - up to 2% of the lubricant; and - 1 to 15% at least one swelling agent, said tablet having a hardness of from 1 kp (9.8N) to 6 kp (58, BN), a brittleness of less than 1%, and which is capable of disintegrating or dissolving in the mouth without chewing in contact with saliva in less than 60 seconds, forming particles of a suspension that are easily swallowed. 2. A tablet according to claim 1 2. The composition of claim 1, comprising 2 or 3 layers. 3. A tablet according to claim 1 A method according to claim 1, characterized in that it comprises 3 layers and only the two outer layers contain at least one active substance. 4. A tablet according to any one of the preceding claims. A method as claimed in 1-3, characterized in that each layer further comprises, based on the weight of each tablet layer, up to 5% permeable agent, up to 5% antistatic agent, up to 20% water-insoluble diluent, up to 15% binder, up to 2 , 6% sweetener, up to 1.3% flavor, up to 0.5% colorant, as such or in admixture. 5. A tablet according to any one of the preceding claims. The pharmaceutical composition according to any of the claims 1-4, characterized in that at least one active ingredient is in a modified release form. 6. A tablet according to any one of the preceding claims. The process according to 1-5, characterized in that the at least one active ingredient is in a crystalline form, or in the form of a core containing a taste-masking coating. A method for producing a tablet as defined in claim 1, 1-6, characterized in that it comprises the following steps; 1. producing at least two types of optionally coated active substance particles; PL 211 301 B1 2. preparation of at least two dry mixtures, each containing tabletting excipients and at least one type of active ingredient particles; 3. pre-pressing at least one of the above-obtained powder mixture with a pressing force of 0.5 to 15 kN; 4. applying the other mixture prepared in Step 2 to the above mixture; 5. optionally pre-pressing the mixture obtained in step 4, with a pressing force ranging from 0.5 to 15 kN; 6. final compression of the pre-formed layers obtained above, with a compression force in the range of 5 to 50 kN, where steps 4 and 5 may optionally be repeated at least once depending on the number of layers of the tablet.